Structure-Based Discovery of GPCR Ligands from Crystal Structures and Homology Models

  • Anirudh Ranganathan
  • David Rodríguez
  • Jens CarlssonEmail author
Part of the Topics in Medicinal Chemistry book series (TMC, volume 30)


The G protein-coupled receptor (GPCR) superfamily constitutes the largest group of human membrane proteins and plays key roles in diverse cellular processes. Major advances in structural biology for GPCRs have provided invaluable insights into ligand recognition and signaling for these important drug targets. Access to high-resolution crystal structures also enables rational ligand design and in silico methods based on atomic-resolution models are likely to play an increasingly important role in future drug development. In this chapter, examples of ligand discovery efforts based on molecular docking screening against GPCR crystal structures will be presented first. Results from these studies suggest that crystal structures can not only guide discovery of ligands but also predict their selectivity and signaling properties. As experimental structures are not available for a large fraction of the superfamily, methods for atomic-resolution modeling of GPCR–ligand complexes could make important contributions to drug discovery. In the second part of the chapter, the state-of-the-art in this area is discussed in light of three community-wide assessments, which have challenged the modeling community to blindly predict GPCR structures. Finally, several recent examples of successful ligand discovery efforts utilizing atomic-resolution models for GPCRs of unknown structure are summarized.


Agonist Antagonist Comparative modeling Drug discovery Fragment-based lead discovery G protein-coupled receptor Homology modeling Molecular docking Structure-based drug design Virtual screening 



5-Hydroxytryptamine, serotonin


Adrenergic receptor


Adenosine receptor


Central nervous system


C-X-C chemokine receptor


Dopamine receptor


Extracellular loop


Fragment-based lead discovery


Fingerprints for ligands and proteins


G protein-coupled receptor


Histamine receptor


High-throughput screening


Interaction fingerprint


Intracellular loop


Monte Carlo


Molecular dynamics


Metabotropic glutamate receptor


Muscarinic receptor


Molecular weight


Negative allosteric modulator




Opioid receptor


Pan-assay interference compounds


Positive allosteric modulator


Parkinson’s disease


Root-mean-square deviation


Smoothened receptor


Trace amine-associated receptor 1


Target immobilized NMR screening


Transmembrane helix



This work was supported by grants from the Swedish Foundation for Strategic Research (ICA10-0098), Swedish Research Council (2013–05708), and the Science for Life Laboratory to J.C. The Sven och Lilly Lawski Foundation supported D.R. with a postdoctoral fellowship. A.R., D.R., and J.C. participate in the European COST Action CM1207 (GLISTEN).


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Authors and Affiliations

  • Anirudh Ranganathan
    • 2
  • David Rodríguez
    • 2
  • Jens Carlsson
    • 1
    Email author
  1. 1.Science for Life Laboratory, Department of Cell and Molecular Biology, Biomedical CenterUppsala UniversityUppsalaSweden
  2. 2.Science for Life Laboratory, Department of Biochemistry and BiophysicsStockholm UniversityStockholmSweden

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